_' High blood pressure is a strong, modifiable, independent risk factor for cardiovascular and renal disease, and was a primary or contributing cause of 11% of U.S. deaths in 2003 (American Heart Association, 2006). The health burden of high blood pressure has persisted despite marked improvements over the past several decades in the identification and treatment of hypertension and risk factors for cardiovascular disease, including high cholesterol (Hajjar &Kotchen, 2003). Psychosocial risk factors such as loneliness, hostility, depressive symptoms, perceived stress, and low/ social support have also been shown to predict high blood pressure and/or hypertension, but distinctions among these psychosocial factors in the mechanisms through which they increase hypertension risk have not been well characterized. Understanding the specificity of associations between psychosocial risk factors and mechanistic pathways through which they act to increase risk of high blood pressure is another frontier along which to wage the battle for control of an ongoing and growing public health problem. In earlier research, we observed that lonely young adults exhibited chronically elevated levels of total peripheral resistance (TPR) relative to nonlonely young adults (Cacioppo, et al., 2002;Hawkley et al., 2003). Increases in TPR are the primary determinant of increases in systolic blood pressure (SBP) until at least age 50. Faster rates of increase in TPR and SBP foster earlier development of arterial stiffening and further increases in SBP, suggesting that-the higher levels of TPR we observed in lonely young adults might, over time, accelerate the development of high blood pressure in lonely individuals. In support of this hypothesis, we found that loneliness was associated with elevated SBP in a population-based sample of older adults aged 50-68 years, and that this association increased as a function of participants'age (Hawkley et al., 2006). Moreover, loneliness was independent of a constellation of related psychosocial factors (i.e., depressive symptoms, perceived stress, hostility, and poor social support) in its association with SBP. In the present project, we propose a cross-sectional study of a population-based sample of young to middle-age adults (26-55 years old) to test whether loneliness is unique in its association with TPR, and to examine five physiological pathways through which loneliness might be related to TPR. We hypothesize that loneliness is associated with TPR through its association with (a) impaired endothelial function, (b) increased oxidative stress, and altered activity of the (c) sympathetic nervous system and (d) hypothalamic-pituitary adrenocortical axis. Identification of plausible mechanisms for the association between loneliness and TPR will set the stage for future longitudinal research that examines the causal role of these mechanisms in explaining how loneliness influences risk for elevated TPR and high blood pressure. PERFORMANCE SITE(S) (organization, city, state) The University of Chicago, Chicago, IL PHS 398/2590 (Rev. 09/04, Reissued 4/2006) Page Continuation Fomiat Page Program Director/Principal Investigator (Last, First, fVllddle): Hawkley, Louise C DETAILED BUDGET FOR INITIAL BUDGET PERIOD DIRECT COSTS ONLY PERSONNEL (Applicant organization only) Months Devoted to Project ROLE ON Cal. Acad. Summer INST.BASE NAME PROJECT Mnths Mnths Mnths SALARY Hawkley, Louise C PD/PI 3 88,000 Cacioppo, John T Co-PI .9 0 Cacioppo, John T Co-PI 1 0 Project TBA 12 40,000 Manager TBA Project Staff 12 40,000 SUBTOTALS CONSULTANT COSTS EQUIPMENT (Itemize) Tonometric Blood Pressure Monitor SUPPLIES (Itemize by category) EKG electrodes. Filter Paper, Blood Tubes, Chemicals $2,250 Computer, Software $2,500 Nitroglycerine, Urine Bottles, Salivettes, $ 945 Comliance Monitors, Glucose &Cholesterol Cartridges $6,615 TRAVEL Pis to professional meetings - PATIENT CARE COSTS INPATIENT OUTPATIENT ALTERATIONS AND RENOVATIONS (Itemize by category) OTHER EXPENSES (Itemize by category) Subject fees, food, transportation $16,920 Assays $38,160 Mailing &Paperwork $2,700 Service Contracts $4,000 Detecto Healthometer $250 Phones $800 CONSORTIUM/CONTRACTUAL COSTS FROM THROUGH 6/01/2009 5/31/2009 DOLLAR AMOUNT REQUESTED (omit cents) SALARY FRINGE REQUESTED BENEFITS TOTAL 22,000 4,818 26,818 14,753 3,231 17,983 16,228 3,554 19,782 40,000 8,760 48,000 40,000 8,760 48,000 132,980 29,123 162,1031 7,500 12,310 2,500 ' 62,830 DIRECT COSTS 42,265 SUBTOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD (Item 7a, Face Page) $ 289,5081 CONSORTIUM/CONTRACTUAL COSTS FACILITIES AND ADMINISTRATIVE COSTS 23,843 TOTAL DIRECT COSTS FOR INITIAL BUDGET PERIOD $ 313,351 PHS 398 (Rev. 11/07) Page. Form Page 4